Acyl-z-halophenyl benzimhj azoles



'helminthiasis.

United States Patent 3,192,227 N-ACYL-Z-HALGPHENYL EENZAZOLES Horace D. Brown, Plainfield, and Lewis H. Sarett, Princeton, N.J., assignors to Merck 8: (10., Inc, Railway, N .J., a corporation of New Jersey No Drawing. Filed July 27, 1961, Ser. No. 127,146 7 Claims. (Cl. 260-6092) This invention relates to compounds useful against It relates more particularly to new ben- Ximidazoles. Still more particularly, relates to l-acyl benzimidazoles having at the 2-position of the nucleus an o-halophenyl radical, and with methods of making such compounds. It relates further to anthelmintic coman active ingredient. This application is a continuation-in-part of our applications Serial Nos. 39,754 and 39,761, filed June 30, 1960, both now abandoned. The infection known as helminthiasis involves infestation of the animal body and particularly the gastro-intestinal tract with various species of parasitic worms. It is a very widespread and serious disease, and the methods heretofore available for its treatment and prevention have not been entirely satisfactory. It is an object of this invention to provide a group of substituted benzimidazoles which are effective in controlling helminthiasis, and which lack many of the objectionable features of the known anthelmintics.

According to the present invention, it has been found that a group of benzimidazoles, having at the 2-position of the benzimidazole ring nucleus an o-halophenyl radical where the halogen has an atomic weight of between 19 and 35.5 inclusive, possess a significant degree of anthelmintic activity and may be effectively employed in the treatment and/or prevention of helminthiasis. It is one object of this invention to provide anthelmintic compositions containing such compounds. Another object is provision of a method of controlling helminthiasis with these substances, A further object is to provide novel l-acyl benzimidazoles substituted at the 2-position with an o-fluorophenyl or o-chlorophenyl radical. A further object is provision of methods of synthesis of such compounds. Still other objects will become apparent from the following description of the invention.

Compounds which, according to our invention, have been found to .possess significant anthelmintic activity may be represented by the structural formula N WK? E i X wherein R can be hydrogen, lower alkyl or lower alkenyl groups, R and R may be either hydrogen, lower alkyl or lower alkoXy, and X is a halogen having an atomic weight of between 19 and 35.5 inclusive, i.e., fluorine or chlorine. The invention also includes within its scope acid addition salts of these benzimidazoles when R is hydrogen.

The N-1 position of the benzimidazoles (R in Formula I) as heretofore mentioned, may be substituted with hydrogen, a lower alkyl group such as methyl, ethyl, propyl or isopropyl, or a lower alkenyl radical of the type represented by allyl and methallyl. It is preferred that the alkyl and alkenyl radicals contain less than 6 carbon atoms. If desired, the six-membered ring of the benzimidazole nucleus may also be substituted with lower alkyl groups or lower alkoxy groups at the 5- and/ or 6-positions. Where there are substituents on the sixice membered ring of the benzimidazole nucleus, methyl or methoxy groups are the preferred substituents, although methyl, ethyl, propyl, methoxy, ethoxy and similar lower alkyl and lower alkoxy radicals, of course, may be employed. However, in the preferred compounds R and R of Formula I represent hydrogen.

As representative of the 2-substituted benzimidazole compounds which are now found to be active anthelmintic I agents and which come within the scope of our invention,

there may be mentioned: 2-(o-fluorophenyl)benzimidazole, 2-(o-chlorophenyl)benzimidazole, N-methyl 2-(o-. fluorophenyl)benzimidazole, N-methyl 2-(o-chlorophenyl)-5-methoxy benzimidazole, N-allyl 2-(o-fluorophenyl)- S-ethoxy benzimidazole, N-propyl 2-(o-fluorophenyl)ben-. zirnidazole, N-allyl 2-(o-chlorophenyl)benzimidazole, 2- (o-fluorophenyl)-5-methyl benzimidazole, 2 (o-chlorophenyl)-5-ethoxy benzimidazole, and the like.

i The 2-substituted benzimidazoles described herein are isolated as the free bases by the synthetic processes normally employed. They are readily converted to acid addition salts by treatment with acid. Typical salts which may be formed in tln's manner are mineral acid salts such as the hydrohalides, e.g. hydrochloride, hydrobromide, hydroiodide, sulfates, nitrates, phosphates, aliphatic acid salts such as the acetate, trimethylacetate, t-butylacetate, or propionate, salts of polycarboxylic acids such as the citrate, oxalate, succinate and the like and salts of other insoluble organic acids such as the embonate and hydroxynaphthoate salts. Certain of these salts are much more water soluble than the free bases. This is true of the hydrohalides. Since the solubility may also be decreased by formation of an appropriate salt, it will be seen that the solubility properties of a particular compound may be generally adjusted by judicious selection of a salt. When the compounds of this invention are used in salt form as anthelmintics, it is, of course, desirable that the particular acid employed be an edible, non-toxic one.

2-(0 fiuorophenyl)benzimidazole and 2 (o chlorophenyl)benzimidazole represent the preferred compounds of the invention. The preparation of these substances and the other 2-(o-luorophenyl)benzimidazoles of Formula I above is carried out by reacting o-fluorobenzaldehyde or o-fiuorobenzoic acid or a derivative of o-fiuorobenzoic acid such as o-fluorobenzamide or lower alkyl o-fluorobenzoate with a compound of the general formula wherein R may be either hydrogen, lower alkyl or lower alkenyl, and R and R may be either hydrogen, lower alkyl or lower alkoxy.

Alternatively, the N-alkyl and N-alkenyl 2-(o-halophenyl)benzimidazoles may be obtained by alkylation or alkenylation of a 2-(o-halophenyl)benzimidazole. If desired, the siX-membered ring of the benzimidazole nu-. cleus may also be substituted as with lower alkyl or lower alkoxy groups at the 5- and/or 6-positions. An alkali metal salt of the 2-(o-halophenyl)benzimidazole is first prepared. This may be done by intimately contacting an alkali metal hydride such as sodium hydride, lithiumhydride or potassium hydride with the 2-(o-halophenyl)- benzimidazole. To form the N-alkyl or N-alkenyl derivatives, the alkali metal salt of the 2-(0-fluorophenyl), benzimidazole or 2-(o-chlorophenyl)benzimidazole is reacted With an alkylating agent such as methyl chloride, ethyl bromide, allyl chloride or cinnamyl chloride, in a suitable solvent such as benzene and/or dimethyl formamide.

The 2 (o fluorophenyl)benzimidazoles and 2 (ochlorophenyl)benzimidazoles described herein have, a high degree of anthelmintic activity and are useful in the treatment and/ or prevention of helminthiasis, a parasitic disease which causes widespread and often serious infection in domesticated animals such as swine, horses, cattle, sheepand goats; In treating domesticated animals, the compounds may be mixed with a non-toxic, edible carrier to form-a feed supplement which is then incorporated in the animal feed inthe desired concentration, or they may be administered in unit dosage forms which, in the case of large domesticated animals, take the form of boluses, or in the form of a liquid drench. Alternatively, water-soluble salts or a dispersable, wettable powder containing the anthelmintic agent may be added to the drinking water of the animals.

The preferred dosage level for treating a helminth infection will depend to a large extent on the particular 2- '(o-halophcnyl)benzimidazole compound being employed, on the severity of the infection and on the particular species of animal to be treated. In general, the 2-(0- chlorophenyl) and 2-(o-fiuorophenyl)benzimidazoles ex-. hibit anthelmintic activity when administered to animals in a daily dose of about 50 to about 300 mg. per kilogram of animal body weight. It is preferred to employ in the range of l200 mg per kilogram of body weight per day. The compounds may be given in a single dose or divided into a plurality of smaller doses. With the compounds of this invention highly satisfactory results in freeing the animal of helminths are achieved by administering the compounds for only a single day at the above levels. If desired, the course of treatment may be extended over a period of days in which case the optimum daily dose level may be lowered. When the compounds are to be employed primarily as prophylactic agents for the prevention of helminthic infections, the preferred daily dose level'is, of course, lower than the therapeutic level and is, preferably in the range of about -70 mg. per kilogram of body .weight. The 2-(o-chlorophenyl)- benzimidazoles may be incorporated in the animal feeds, and this method of administration is preferred when the compounds are to be used prophylactically, in which case they are incorporated in the feeds at concentrations such that theanimal will consume daily from about 10 to about 70 mg. of 2-(o-chlorophenyl)benzimidazole per kilogram of body Weight.

' The means employed for administering these benzimi'dazoles to animals are not critical, and any of the methods now used or available for treating animals infected with or susceptible to parasitic infections are satisfactory. When these substances are employed therapeutically to treat an established infection, they are conveniently administered'in a unit dosage form suchas in a capsule, bolus, tablet, or as a liquid drench. It will be noted that all of these methods contemplate oral administration, since this is the most effective method of treating the worm-infested stomach .or intestinal tract.

' When the 2-(o-chlorophenyl) or 2-(o-fluorophenyl)- benzimidazoles are to be administered in unit dosage form, capsules, boluses or drenches containing the desired amount of anthelmintic distributed in a pharmaceutically acceptable vehicle are usually employed. These are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, suspending agents, fillers, disintegrating agents and/ or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. These unit dosage formulations may be widely varied with respect to their total weight and content of anthelmintic agent, depending on factors such as the type of host animal to be treated, the dose level desired, and the severity and type of parasitic infestation. For large animals such as sheep, swine or cattle, boluses weighing up to grams may be used, although it is preferred to employ boluses weighing from 2-10 grams and containing from 1-5 grams of the anthelmintic agent. These boluses, as well as smaller size tablets, contain binders and lubricants, and are compounded by techniques knownrin this art. Capsules are readily prepared by mixing the active ingredient with a diluent such as starch or lactose and filling into the capsule.

In order to treat infected animals by means of a drench, the 2-(o-halophenyl)benzimidazoles are mixed with a suspending agent such as bentonite and the solid product added to Water just prior to administration. Alternatively, ready-to-use drench formulations, such as those disclosed in US. Patent No. 2,918,403 are sometimes utilized. The preferred drenches in accordance with this invention contain from about 550% by weight of 2-(0- halophenyl)benzimidazole compound.

The 2-(o-halophenyl)benzimidazoles described herein may also be administered as a component of the feed of the animals or dissolved or suspended in the drinking According to the invention, novel feed and feed water. supplement compositions are provided in which compounds of Formula I above are present as an active anthelmintic ingredient. Such compositions comprise the benzimidazoles intimately dispersed in or admixed with an inert carrier or diluent, i.e., one that is nonreactive with respect to the 2-(o-ha1ophenyl)benzimidazole and that may be administered with safety to the animals. The carrier or diluent is preferably one that. is or may be an ingredient of the animal ration.

In the feed supplement compositions the active ingredient is present in relatively large amounts. These supplements are suitable for addition to the .feed either directly or after an intermediate dilution or blending step. Examples of carriers or diluents suitable'for such compositions are solid orally ingestible carriers such as distillers dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled .soya flour, soybean mill feed, antibiotic mycelia, soya grits, crushed limestone and'the like. The anthelmintic agents are intimately dispersed or admixed throughout the solid inert carrier by methods such as grinding, stirring, milling, or tumbling. By selecting properv diluentsv and by altering the ratio of carrier to active ingredient, compositions of any desired concentration may be prepared. Formulations containing from about 5% to about 50% by weight, and preferably from about 10-30% by weight, of active ingredient are particularly suitable for addition to feeds. The active compound is normally dispersed or mixed uniformly in the diluentbut in some instances may be sorbed on the carrier.

Examples of typical feed supplements containing the 2 -(o-halophenyl)benzimidazole dispersed in a solid carrier are:

Lbs. 2-(o-chlorophenyl)benzimidazole 20.0 Corn distillers dried grains 80.0

B. 2-(o-fluorophcnyl)benzimidazole hydrochloride 5.0 Wheat standard middlings 95.0

C. 2-(o-chlorophenyl)-5-methoxy benzimidazole 35.0 Wheat shorts 65.0

, D. N-methyl-2-(o-fluorophenyl)benzimidazole 50.0 Corn distillers grains 50.0

These and similar feed supplements are prepared by uniformly mixingthe appropriate 2-(o-halophenyl)benzimidazole with the carrier or. carriers. Such supplements are added to the finished animal feed in an amount adequate to give the finalconcentration desired for controlling or treating helminthiasis by way of the animal ration. Although the preferred level -in feeds will depend on the particular compound being employed, the anthelmintic acyl halide.

5 compounds of this invention are normally fed at levels of 0.l-2.0% in the feed. One advantageous method of administering the compounds of this invention to animals 'whose feeds are conveniently pelleted, such as sheep, is

to incorporate them directly in the pellets. For instance, 2-(o-chlorophenyl)benzimidazole is readily incorporated in nutritionally adequate alfalfa pellets (during the pelleting operation) at levels of 0.5 to grams per pound of pellets for therapeutic use, and at lower levels for prophylactic use, and such pellets fed to the worm-infested animals. Alternatively, the 2-(o-halophenyl)benzimidazoles may be incorporated in salt licks or salt blocks at any desired concentration (concentrations of 525% by weightare conveniently employed). Large animals, such as sheep, cattle and goats, then receive the anthelmintics with their salt.

In accordance with an additional aspect of this invention, it has been discovered that novel N-acyl 2-(o-halo-, phenyl)benzimidazoles, where the halo radical has an atomic weight of between 19 and 35.5 inclusive, are also highly active anthelmintic agents. Such compounds may be represented by the formula Br I N \NlQ where X is a halogen having an atomic weight of between 19 and 35.5, inclusive (i.e. fiuoro and chloro), R and R are hydrogen, lower alkyl or lower alkoxy, and R is an acyl radical.

These novel N-acyl benzimidazoles are prepared from the parent 2-(o-halophenyl)benzimidazole by forming an alkali metal salt thereof, and reacting such salt with an The salt-is produced by reacting the benzimidazole with an alkali metal hydride such as sodium or potassium hydride. This compound is then treated, without isolation, with'an aroyl halide or a lower alkanoyl halide such as acetyl chloride, acetyl bromide, propionyl chloride, butyroyl bromide, or benzoyl chloride to form the corresponding N-acyl 2-(o-halophenyl)benzimidazole. In this way there are produced novel acylbenzimidazoles such as N-acetyl 2-(o-chlorophenyl)benzimidazole, N-benzoyl 2-(o-fluorophenyl)benzimidazole, N-propionyl 2-(o-fluorophenyl)-5-methoxy benzimidazole, N-benzoyl- 2-(o-chlorophenyl)-5-methoxy benzimidazole and N- acetyl 2 (o chlorophenyl) 5 methyl benzimidazole. These compounds are highly potent anthelmintics. When used for the treatment or prevention of this disease, they are formulated and administered as boluses, capsules, drenches, or in the feed as described in detail above for the benzimidazoles of Formula I.

The following examples are given for the purpose of illustration and not by way of limitation:

EXAMPLE 1 The N-acylated 2-(o-chlor-ophenyl)benzimidazoles are obtained by reacting together an alkali metal salt of 2- (o-chlorophenyl)benzimidazole and an appropriate acyl halide. Thus, N-acetyl 2-(o-chlorophenyl)benzimidazole is made in the following manner:

A. A2.l g. sample of 2-(o-chlorophenyl)benzimidazole is added to a mixture of 50 ml. of toluene and mlof dimethylformamide in a round-bottom' flask. The suspension is then dried by azeotropic distillation of a small amount of the toluene, and a suspension of 0.7 g. of 52% sodium hydride in 5 ml. of toluene is then added thereto. The mixture is heated to 60 C. (hydrogen is evolved) and stirred at 60 C. for one hour. A 1 g. portion of acetyl chloride is then added dropwise. The yellow color of the sodium salt is rapidly discharged. After an additional stirring period of one hour, the

solution is cooled, a small volume of water is added and the organic phase is separated, washed with water, dried over sodium sulfate and concentrated in vacuo to give a residue of l-acetyl 2-(o-chlorphenyl)benzimidazole. This product is further purified by recrystallizing from a small volume of ethyl acetate or from a mixture of etherpetroleum ether.

B. l-benzoyl 2-(o-chlorophenyl)benzimidazole is made by reacting together 0.05 M of benzoyl chloride and 0.05 M. of the sodium salt of 2-(o-chlorophenyl) benzimidazole by the procedure of part A above.

C. By intimately contacting the sodium salt of 2-(0- chlorophenyl)benzimidazole with propionyl chloride, benzoyl bromide, p-chlorobenzoyl chloride and isobutyroyl chloride according to the process set forth for making 1- acetyl 2(o-chlorophenyl)benzimidazole,. there are obtained respectively the N-propionyl, benzoyl, p-chlorobenzoyl and isobutyroyl 2-(o-chlorophenyl)benzimidazoles. In some cases, one recrystallization does not yield substantially pure material. Such compounds are further purified by chromatography on neutral alumina, and elution of the desired N-acetyl 2-(o-chlorophenyl)benzimidazole with ether or ethyl acetate.

EXAMPLE 2 1 -pr0pi0nyl 2-( o-chlorophenyl) -5-metlt0xy benzimidazole 2.1 g. of 2-(o-chlorophenyl)-5-methoxy benzimidazole is added to a mixture of 50 ml. of toluene and 15 ml. of dimethylformamide in a round-bottom flask. The suspension is then dried by azeotropic distillation of a small amount of the toluene. A suspension of 0.7 g. of 52% sodium hydride in 5 ml. of toluene is then added to the above-mentioned solution. The mixture is stirred at 60 C. for one hour, and then '1 g. of propionyl chloride is added dropwise. The yellow color of the sodium salt is rapidly discharged. After an additional stirring period of one hour, the solution is cooled, a small volume of Water is added, and the organic phase is separated, washed with water, dried over sodium sulfate and concentrated in vacuo to give l-propionyl 2-(o-chlorophenyl)-5-methoxy benzimidazole. This product is further purified by recrystallization from a small solution of ethyl acetate.

EXAMPLE 3 N-acyl 2-(o-chlorophenyl) benzimidazoles are obtained by reacting together an alkali metal salt of Z-(fluorophenyl)benzimidazole and an appropriate acyl halide. Thus, N-acetyl 2-(o-finorophenyl)benzimidazole is made in the following manner:

To 9.7 g. of 2-(o-fluorophenyl)benzimidazole in 100 ml. of dry dimethylform amide is added 23 g. of a "52% sodium hydride emulsion in mineral oil. The mixture is stirred at room temperature for about 20 minutes and then warmed carefully to about 50 C. for :10 minutes.-

It is cooled to room temperature and 1.6 g. of acetyl chloride in 10 ml. of dimethylformamide is added slowly to the cooled solution. The reaction mixture is then heated to about C. for 20 minutes, cooled, diluted with 200 ml. of Water and extracted with three -rnl. portions of ether. The ether extracts are combined, washed with water, dried over sodium sulfate, filtered and ether removed in vacuo to give l-acetyl Z-(o-fluorophenyl) benzimidazole.

By intimately contacting the sodium salt of 2-(o-fluorophenyl)benzimidazole with acetyl bromide, propionyl chloride, hexanoyl chloride and benzoyl chloride according to the process set forth above for making N-acetyl 2-(o-fluorophenyl)benzimidazole, there are obtained respectively the N-acetyl, N-propionyl, N-hexanoyl and N- benzoyl 2-(o-fiuorophenyl)benzimidazoles. The compounds are purified by recrystallization or by chromatography on neutral alumina.

EXAMPLE 4 2-(o-fiuorophenyl)benzimidazole, when fed orally to J a, 92,222 H 7 I 8- mice infected with Nematospiroides dubius, preventedt {EXAMPLE 7 nematode larval development at dose levels of 31, 62,.

125, 250 and 500 mg./kg. 2-(o-chlorophenyl)benzimid azole was effective in preventing nematode larval develop-- mcnt at levels of 62, 250 and 500 mg./l g.

EXAMPLE 5 Boluses of 2-(o-fiuorophenyl)benzimidazole or 2-(o chlorophenyl)benzimidazole suitable for oral. administra-- A. To prepare (A) above, the dicalcium phosphate is thoroughly mixed with the Z-(o-halophenyl)benzimidazole and the mixture reduced to a particle size finer than 60 mesh. To the mixture is added 0.330 g. of starch in the form of an aqueous starch paste and the resulting mixture granulated in the usual manner. The granules are then passed through a No. mesh screen and dried at l10-130 F. for about 8 hours, and the dried material then pased through a No. 16 mesh screen. The guar gum and the balanceof the starch are added and the mixture thoroughly blended. The remainder of the ingredients are .then added and the whole thoroughly mixed and compressed.

B. Preparation (B) is made by thoroughly mixing the dicalcium phosphate with the 2-(o-halophenyl)benzimidazole and reducing themixture to a particle size finer than 60 mesh. To the mixture is added 0.430 g. of starch in. the, form ofan aqueous starch paste and the resulting mixture is then granulated in the usual manner. The granules are passed through a No. 10 mesh screen and dried at 110-130" F. for about 8 hours, and the dried material then passed througha No. 16 mesh screen. The guar gum and the balance of the starch are added and the mixture thoroughly blended. The remainder of the ingredients are then added and the whole thoroughly mixed and compressed.

EXAMPLE 6 A tablet having the following composition:

. s N-rnethyl 2-(o-fiuorophenyl)benzimidazole 125 Dicalcium phosphate 250 Starch 125 Guar gum (60 mesh) 17 Talc (60 mesh) 14 Magnesium stearate (60 mesh) 5 is prepared in the following manner:

The dicalcium phosphate, N-methyl 2-(o-fiuorophenyl) benzimidazole and 50 mg. of starch are thoroughly mixed and the mixture reduced to a particle size finer than 60 mesh. 45 mg. of starch in the form of an aqueous starch paste is added to the mixture and the whole granulated in the ,usual manner. The granules are then passed through a No. 10 mesh screen and dried at 110-130 F. for about 8 hours. The dried material is then passed through a No. 16 mesh screen. The guar gum and the balance of the starch are added and the mixture thoroughly blended. The remainder of the ingredients are then added and the mass mixed and compressed.

Tablets containing 2-(o-chlorophenyl)benzimidazole as the active anthelmintic agent are prepared in a similar manner.

.Drenches Ihaving'the following composition are .prepared by standard formulating methods:

2-(o-fluorophenyl)benzimidazole gm 2.3 Antifoam AF?emulsion. gm 0.06 Hydroxyethyl cellulose 'gm 0.3 Sodium phosphate 'monobasic gm 0.3

10 Benzalkonium chloride '(l2.8 %sol'n.) 'r ril Water "m1 'tO 30.0

N-benzoyl 2-(o-chlorophenyl)benzimidazole. gm I 4.0

Antifoam AF'emulsion 'gm 0.06 Hydroxyethyl cellulose "gm" 0.3 Sodium phosphate monobasic gtn 0.3 Benzalkoniurn-chloride-(l2;8% soln.) inl 0.6 Water 'ml to 30.0

Drenc-hes may also be prepared in bulk for subdivision prior to use. The following vehiclesare suitable:

Benzalkonium chloride (12.8% soln.) ml

Antifoam AF emulsion gm 4 Hydroxyethyl cellulose gm 20 Distilled water o ml to 2000 Benzalkonium chloride (12.8% 80111.) nil 0.5 Antifoam AF emulsion gm 1 Hydroxyethyl cellulose 'gm 2 0 Distilled water ml to 2000 o The compounds of Formula I above are added to the vehicles in concentrations in the range of 15-40 gm./ 100 ml. The benzalkonium chloride used in the drench vehicles as a mixture of C C dimethylbenzylammonium chlo- 40 rides. 7

Any departure from the above description which con; forms to the present invention is intended to be included within the scope of the claims.

' What is claimed is:

4r} 1. A compound having the formula 5 wherein R and R are selected from the class consisting of hydrogen, lower alkyl and lower alkoxy', R is selected from the class consisting of benzoyl and lower alkarioyl, and X 18 halogen having an atomic weight of between 19 and 35.5 inclusive.

6O 2. N-acetyl 2-(o-chlorophenyl)benzimidazole.

3.l-I-benzoyl 2-(o-chlorophenyl)-5-rnethoxy benzimidazole.

4. I N-acetyl 2-(o-fluorophenyl)benzimidazole.

5. N-benzoyl 2-(o-fluorophenyl)benzimidazole.

6. Tl 1e process for preparing a Z-(o-haIOphenyI) N-acyl benzimrdazole having the structure wherein R and R are selected from the class consisting of hydrogen, lower alkyl and lower alkoxy, R is selected from the class consistin' of benzoyl and lower alkanoyl, and X is halogen having an atomic weight-of between 19 to 35.5 inclusive, that comprises the step of reacting an alkali metal salt of a compound of the structure W L N wherein R R and X are as defined above, with an acylating agent of the class consisting of benzoyl and lower alkanoyl halide.

7. The process for the production of N-benzoyl 2-(0- fluorophenyDbenzimidazole that comprises reacting the sodium salt of 2-(o-fluorophenyl)benzimidazole wi benzoyl chloride. 7 7

10 References Cited by the Examiner UNITED STATES PATENTS 2,956,923 10/60 Kent 26O53 2,971,885 2/61 Luther et a1. 260-53 2,985,661 5/61 Hein et a1. 260309.2 3,029,236 4/62 Staeuble et a1. 260-249.5 3,080,282 3/63 Shunk 260-309.2

OTHER REFERENCES IRVING MARCUS, Primary Examiner.

DUVAL T. MCCUTCHEN, NICHOLAS S. RIZZO,

WALTER A. MODANCE, Examiners. 

1. A COMPOUND HAVING THE FORMULA
 6. THE PROCESS FOR PREPARING A 2-(O-HALOPHENYL) N-ACYL BENZIMIDAZOLE HAVING THE STRUCTURE 